BE897864A - PROCESS FOR PRODUCING 7-SUBSTITUTED 3-VINYL-3-CEPHEM COMPOUNDS AND NOVEL PRODUCTS THUS OBTAINED - Google Patents

Abstract

Syn isomers of compound having the formula (I), wherein R1 is the amino group or a protected amino group, and R2 is the carboxy group or a protected carboxy group, and their pharmaceutically acceptable salts are useful as antibacterial agents vis- against Gram-positive and Gram-negative bacteria.

Description

       

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   PATENT OF INVENTION In the name of: FUJISAWA PHARMACEUTICAL CO., LTD.



   Osaka (Japan) Pros: Process for the production of 3-vinyl-3-cephem-7-substituted compounds and new products thus obtained.



  Priorities: patent application filed in the United States of America on September 30, 1982 under number 428. 970 in the name of the inventors whose plaintiff is the beneficiary and in Great Britain on August 26, 1983 under number 8323034 name of the Applicant.



  Inventors: Takao TAKAYA
Hisashi TAKASUGI
Takashi MASUGI
Hideaki YAMANAKA
Kohji KAWABATA

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The present invention relates to new compounds of 3-vinyl-3-cephem 7-'substituted and to a pharmaceutically acceptable salt of these compounds.



   More particularly, it relates to new 7-substituted 3-vinyl-3 cephem compounds and to a pharmaceutically acceptable salt of these compounds, which have antimicrobial activity, to processes for the production of these compounds, to a pharmaceutical composition. including them, and to a method for the treatment of infectious diseases caused by pathogenic microorganisms comprising administering these compounds to infected humans or animals.



   It is therefore an object of the present invention to provide new 7-substituted 3-vinyl-3 cephem compounds and a pharmaceutically acceptable salt of these compounds, which are highly active against a number of pathogenic microorganisms and are useful as agents antimicrobials, especially for oral administration
Another object of the present invention is to provide processes for the production of new 3-vinyl-3-cephem 7-substituted compounds and a salt of these compounds,

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Another object of the present invention is to provide a pharmaceutical composition comprising, as active ingredients, these 7-substituted 3-vinyl-3-cephem compounds and a pharmaceutically acceptable salt of these compounds.



   Yet another object of the present invention is to provide a method for the treatment of infectious diseases caused by pathogenic microorganisms which comprises administering these 7-substituted 3-vinyl-3-cephem compounds and a pharmaceutically acceptable salt of these compounds to humans or infected animals.



   The 7-substituted 3-vinyl-3-cephem compounds according to the present invention are new and can be represented by the following general formula (I)
 EMI3.1
 where R1 is the amino group or a protected amino group, and
 EMI3.2
 2 is the carboxy group or a protected carboxy group.



   It should be understood that the expression "syn isomer" used in the present description means the compound (I) having the partial stereospecific structure of formula:
 EMI3.3
 
Suitable pharmaceutically acceptable salts of the desired compound (1) are conventional non-toxic salts and can comprise a salt with a base or an addition salt with acids, such as a salt with a mineral base, for example a salt of alkali metal (for example $ Odium salt, potassium salt, etc.), an alkaline earth metal salt (for example calcium salt, magnesium salt, etc.), an ammonium salt;

   a salt with an organic base, for example an organic amine salt (for example-

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 ple triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzyl ethylenediamine salt, etc.). ; an addition salt with mineral acids (for example hydrochloride, hydrobromide, sulphate, phosphate, etc.); an addition salt with organic carboxylic or sulfonic acids (for example formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (for example arginine, aspartic acid, glutamic acid, etc.); and the like.



   The desired compound (I) or a pharmaceutically acceptable salt of this compound of the present invention can be produced by the methods illustrated below.



   (1) process 1:
 EMI4.1
 (II) or its salt
 EMI4.2
 
 EMI4.3
 (I) or its salt (2 Method 2
 EMI4.4
 

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 EMI5.1
 Removal of the radical protection group
 EMI5.2
 carboxy --- rR- / r Il \ (Ib)
 EMI5.3
 or its salt (3) Method 3:

   
 EMI5.4
 
 EMI5.5
 (Ib) or its reactive derivative on the carboxy group or its salt Introduction of the radical protection group
 EMI5.6
 carboxy --------- "-" R2 a a (Ia)
 EMI5.7
 or its salt (4) Method 4
 EMI5.8
 
 EMI5.9
 or its salt

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 EMI6.1
 Removal of the radical protection group
 EMI6.2
 carboxy b 1, -C-CONH --- VIN -> R fi 1-1-S CH = CH carboxy R-. - He
 EMI6.3
 (rd) or its salt 1 2 In these formulas and are each as defined above, X is a halogen, 2 R is a protected carboxy group, a R5 is a carboxy protected alkoxy group b (lower) carbonyl and 2 is a carboxyalkoxy group c carbonyl.



  As regards the starting compound (II) used in method 1, this compound (II) is new and can be prepared, for example, by the following methods.



  Method A:
 EMI6.4
 
 EMI6.5
 or its reactive derivative on the carboxy group or its salt
 EMI6.6
 R-OH (V) or its reactive derivative on the hydroxy group or its salt s -N '- CH = CH o COOR
 EMI6.7
 or its salt

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 EMI7.1
 Method B:
 EMI7.2
 
 EMI7.3
 or its derivative on the amino group, or its salt
 EMI7.4
 X-CHCOCHCOOK (VI) 8 - its reactive derivative on the carboxy group or its salt XCH2COCH2CON -NJ - CH = CH R2
 EMI7.5
 or its salt
 EMI7.6
 0 (0 Nitrosating agent if XCH COCCONH 2 and r N J J - CH = CH S 0 OH
 EMI7.7
 or its salt In these different formulas, and X are each as defined above and the group "COOR" is a protected carboxy group.



  In the above and subsequent descriptions of the present invention, examples and suitable illustrations of the various definitions which the present invention includes in its field of protection are explained in detail as follows, The term "lower" is to be signified 1

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    : 6 carbon atoms, unless otherwise indicated.



   The term "superior" is intended to mean 7 to 20 carbon atoms, unless otherwise indicated.



   The suitable "protected amino" group may include an amino group substituted with a conventional amino radical protecting group which is used in the penicillin and cephalosporin compounds, for example an acyl group as mentioned below, lower aralkyl such as a lower mono- (or di or tri) phenylalkyl group (for example benzyl, benzhydryl, trityl, etc.), a lower (lower) carbonylalkylidylene alkoxy group and its enamine tautomer (for example
 EMI8.1
 group I-methoxycarbonyl-1-propen-2-yl, etc.), a dialkyl group (lower) (for example the dimethylaminomethylene group, etc.), etc.



  A suitable "acyl" group may include an aliphatic acyl group, an aromatic acyl group, a heterocyclic acyl group and an aliphatic acyl group substituted by one or more aromatic or heterocyclic groups.



   The aliphatic acyl group may include acyclic or cyclic groups, saturated or unsaturated, such as a lower alkanoyl group (for example the formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, iseryleryl, pivaloyl, hexanoyl groups, etc.), alkane (lower) sulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.), alkoxy (lower) carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc.) lower alkenoyl (for example the acryloyl, methacryloyl, crotonoyl groups, etc.), a cycloalkane (C 1 -C) carbonyl group (for example, the cyclohexanecarbonyl group, etc.),

     the amidino group and the like,
The aromatic acyl group may include an aroyl group (e.g., benzoyl, toluoyl, xyloxyl, etc.), an arenesulfonyl group (e.g., benzenesulfonyl, tosyl, etc.) and the like.

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   The heterocyclic acyl group may include a heterocyclic carbonyl group ((e.g., furole, thénoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, tetrazolylcarbonyl group, etc.) and the like.



   The aliphatic acyl group substituted by one or more aromatic groups can comprise a lower aralkanoyl group such as a lower phenylalkanoyl group (for example the phenylacetyl, phenylpropionyl, phenylhexanoyl groups, etc.), aralkoxy (lower) carbonyl such as a phenylalkoxy group (lower) carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), a lower phenoxyalkanoyl group (e.g., phenoxyacetyl, phenoxypropionyl, etc.), and the like.



   The aliphatic acyl group substituted by one or more heterocyclic groups can comprise a thienylacetyl, imidazolylacetyl, furylacetyl, tetra-
 EMI9.1
 zolylacetyl, thiazolylacetyl, thiadiazolylacetyl, thienylpropionyl, thiadiazolylpropionyl, and the like.



   These acyl groups can be further substituted by one or more suitable substituents such as a lower alkyl group (for example methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, etc.), a halogen (for example chlorine, bromine, iodine, fluorine), a lower alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, etc.), a lower alkylthio group (e.g. methylthio groups , ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, etc.

   ), the nitro group and the like, and a preferable acyl group having this or these substituents may be a lower mono (or di or tri) haloalkanoyl group (for example the chloroacetyl, bromoacetyl, dichloroacetyl, tri:

   fluoroacetyler etc,), a mono group Cou di or tri) haloalkoxyCinfêrieur) carbonyl (. for example chloromethoxycarbonyl, dichloromethoxycarbonyl, 2,2, 2-'trichloroethoxycarbonyl, etc.), a nitro group (or

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 EMI10.1
 halo or lower alkoxyphenylalkoxy ¯ényielcqxy Cne. e) ieui) çç i le (for example nitrohenzylgxycarbonyle chlorobenzyloxycarbonyle, méthQxybenzyloxycarhQnyle, etc.

   ) and the like,
 EMI10.2
 The group "carboxy and the suitable" carboxy protected "part (lower) carbonyl alkoxy" can comprise an esterified carboxy group which is conventionally used in a penicillin or cephalosporin compound, The "ester part" suitable in the "esterified carboxy group" may include a lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester , t-pentyl ester, hexyl ester, etc.), a lower alkenyl ester (for example vinyl ester, allyl ester, etc.), a lower alkynyl ester (for example ethynyl ester, propynyl ester, etc.

   ), a lower alkyl (lower) alkyl ester (e.g. methoxymethyl ester, ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.) lower alkyl (lower) thioalkyl (for example methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.), a lower alkyl ester substituted by carboxy (for example carboxymethyl ester, 2-carboxyethyl ester, 3-carboxypropyl ester, ec.

   ), a lower alkyl ester with protected carboxy substitution such as a lower alkyl ester with lower alkoxy carbonyl substitution (for example the t-butoxycarbonylmethyl ester, the 2-t-butoxycarbonylethyl ester, the 3-t-butoxycarbon ester) bonylpropylic, etc.), a lower mono (or di or tri) haloalkyl ester (for example 2odoethyl ester, 2,2,2-trichloroethyl ester, etc.), a lower alkanoyl (lower) oxyalkyl ester (for example the acetoxymethyl ester, the propionyloxymethyl ester, the butyryloxymethyl ester, the valeryloxymethyl ester, the pi ester,

  <Desc / Clms Page number 11>

 valoxyloxymethyl, hexanoyloxymethyl ester, l (or 2) -acetoxyethyl ester, ester l (or 2 or 3)

  -acetoxypropyl, ester l (or 2 or 3 or 4) acetoxybutyli que, ester l (or 2) -propionyloxyethyl, ester l (or 2 or 3) -propionyloxypropylic, ester l (or 2) -butyryloxyethyl ester l (or 2) -isobutyryloxyethyl ester 2 (or 2) -pivaloxyloxyethyl ester l (or 2) -hexa- peryloxyethyl ester isobutyryloxymethyl ester 2-ethylbutyryloxymethyl ester, ester 3, 3-dimethylbutyryloxymethyl, ester 1 (or 2) -pentanoyloxyethyl, etc.), a lower oxyalkyl higher alkanoyl ester (for example heptanoyloxymethyl ester, octanoyloxymethyl ester, nonanoyloxymethyl ester, decanoyloxymethyl ester, undecanoyloxymethyl ester,

   lauroyloxymethyl ester, tridecanoyloxymethyl ester, myristoyloxymethyl ester, pentadecanoyloxymethyl ester, palmitoyloxymethyl ester, heptadecanoyloxymethyl ester, stearoyloxymethyl ester, nonadecanoyloxymethyl ester, ethyl ester l (or 2) -heptanoyloxyethyl, ester l (or 2) -octanoyloxyethyl, ester l (or 2) -nonanoyloxy- ethyl, ester l (or 2) -decanoyloxyethyl, ester l (or 2 ) -undecanoyloxyethyl, ester l (or 2) -lauroyloxyethyl, ester l (or 2) -tridecanoyloxyethyl, ester l (or 2) -myristoyloxyethyl, ester 11 or 2) pentadecanoyloxyethyl, ester l (or 2) -palmitoyloxy- ethyl, ester 1 (or 2) -heptadecanoyloxyethyl, ester 1 (or 2) -stearoyloxyethyl,

   the l (or 2) -nonadecanoyloxyethyl ester, the l (or 2) -eicosanoyloxyethyl ester, etc.], a lower carbonyloxyalkyl (lower) alkoxy ester [for example the methoxycarbonyloxymethyl ester, the ethoxycarbonyloxymethyl ester, the ester propoxycarbonyloxymethyl, estisopropoxycarbonyloxymethyl,
 EMI11.1
 t-butoxycarbonyloxymethyl ester l (or 2) -methoxycarbonyloxyethyl ester, oxyethyl ester, ester l ester ltou Kou rbonyloxyethyl ester, Kou ester

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 (or 2) -ethoxycarbonyl-toxycarbonyloxyethyl, ester l (or 2) -t-butoxycar- bonyloxyethyl, ester Itou 2) -hexyloxycarbonyloxy- ethyl, ester l (or 2 or 3) -methoxycarbonyloxypropylic, l ' ester l (or 2 or 3)

  -ethoxycarbonyloxypropylic ester l (or 2 or 3) -isopropoxycarbonyloxypropylic ester l (or 2 or 3 or 4) -ethoxycarbonyloxybutyl ester l (or 2 or 3 or 4) -butoxycarbonyloxybutyl ester L (or 2 or 3 or 4 or 5) -pentyloxycarbonyloxypentyle, ester l (or 2 or 3 or 4 or 5) -neopentyloxycarbonyloxypentyle, ester l (or 2 or 3 or 4 or 5 or 6) ethoxycarbonyloxyhexy, etc.], a lower alkyl ester (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) [for example the ester (5-methyl-2-oxo-1, 3-dioxol-4 -yl) methyl, the ester (5-ethyl-2-oxo-l, 3-dioxol-4-yl) methyl, the ester (5-propyl-2-oxo-l, 3-dioxol-4-yl ) ethyl, etc.

   J, a lower alkane sulfonylalkyl ester (for example the mesylmethyl ester, the 2-mesylethyl ester, etc.), a lower aralkyl ester which may have one or more substituents such as a mono (or di or tri) lower phenylalkyl which may have one or more suitable substituents (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, benzhydrylic ester, trityl ester, l bis (methoxyphenyl) methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-t-butylbenzyl ester, etc.

   ), an aryl ester which may have one or more suitable substituents (e.g. phenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicylic ester, etc.), a heterocyclic ester (e.g., phthalidyl ester, etc.), and the like.



     Suitable "halogen" can include chlorine, bromine, iodine and the like,
 EMI12.1
 A group in nyle "and" carboxyalkoxy carbonyl "include the group methoxycarbonyl, ethoxycarbonyl, carbonyl, and the like,

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 EMI13.1
 The suitable group "alkoxy carbony1oxya.

   include methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, (or 2) bonyloxyethyl, (or 2) -ethoxycarbonyloxyethyl, "(lower) alkoxycarbonyl" (or 2) -propoxycarbonyloxyethyl, 1 (or 2) -isopropoxyethyl or 2) -butoxycarbonyloxyethyl, l (or 2) -isobutoxycarbonyloxyethyl, l (or 2) -t-butoxy- carbonyloxyéthyje, l (or 2) -hexyloxycarbonyloxyethyl, l (or 2 or 3) -methoxycarbonyloxypropyle, l (or 2 or 3 ) - ethoxycarbonyloxypropyle, l (or 2 or 3) -isopropoxycarbonyloxypropyle, l (or 2 or 3 or 4) -ethoxycarbony1oxybuty- le, l (or 2 or 3 or 4) -butoxycarbonyloxybutyle, 1 (or
 EMI13.2
 2 or 3 or 4 or 5) -pentyloxycarbonyloxypentyle,

   (or 2 or 3 or 4 or (or 2 or 3 or 4 or 5 or 6) and the like.



   Other preferred embodiments of the desired compound (I) are as follows.



   A preferable example of R1 is
 EMI13.3
 2 the amino group; and is the carboxy group or an esterified R2carboxy group [more preferably a lower carbonyl alkoxy group substituted by carboxy, a lower carbonyl alkoxy group substituted by lower alkoxy carbonyl, an alkanoyl (lower) oxyalkoxy (lower) carbonyl group, an alkanoy group] (upper) oxyalkoxy (lower) carbonyl, an alkoxy group (lower) carbonyl-
 EMI13.4
 oxyalkoxy (lower) a group (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) alkoxy an aralkoxycarbonyl group (for example a diphenylalkoxy group the carbonyl group, phthalidyloxycarbonyl),
Processes for the production of compound (I)

   or its salt will be explained in detail as sult.



  (1) method 1;
Compound (I) or its salt can be produced by reacting compound (II) or its salt with the compound

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 (III).



   A suitable salt of the compound (IT can comprise the same salt with a Base as that indicated by way of example for the compound (I).



   This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as ethyl acetate, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, water, acetic acid, formic acid, etc. or their mixture.



   The reaction temperature is not critical and the reaction is usually carried out at a temperature from cooling to heating.



  Method 2:
The compound (Ib) or its salt can be produced by subjecting the compound (la) or its salt to the reaction for removing the protecting group from the carboxy radical.



   Suitable salts of the compounds (Ia) and (Ib) can include the same as those indicated by way of example for the compound (I).



   A suitable process for this removal reaction can include a conventional process such as hydrolysis, reduction or the like, (i) For hydrolysis:
The hydrolysis is preferably carried out in the presence of an acid.



   A suitable acid can be a mineral acid (for example hydrochloric acid, hydrobromic acid, sulfuric acid, etc.), an organic acid (for example formic acid, acetic acid, trifluoroacetic acid - tick, propionic acid, methanesulfonic acid, oenzenesulfonic acid, p-toluenesulfonic acid, etc.), an acid ion exchange resin and the like.



  In the case where organic acid such as trifluoroacetic acid and p-toluenesulfonic acid are used in this reaction, the reaction is preferably carried out in the presence of cation trapping agents (for example

  <Desc / Clms Page number 15>

 example, anisol, etc.).



   In addition, instead of the above acid, a Lewis acid such as boron trifluoride, boron trifluoride etherate, aluminum trichloride, antimony penachloride, chloride ferric, stannic chloride, titanium tetrachloride, zinc chloride and the like can also be used in this reaction and, in the case where a Lewis acid is used, the reaction can preferably be carried out in presence of a cation imprisonment agent (eg ani- soil).



   The hydrolysis is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, t-butyl alcohol, tetrahydrofuran, N, N-dimé - thylformamide, N, N-dimethylacetamide, dioxane or their mixture and in addition the acids mentioned above can also be used as solvent when they are in the liquid state.



   The reaction temperature of this hydrolysis is not critical, and the reaction is usually carried out at a temperature ranging from cooling to a somewhat elevated temperature.



   (ii) For the reduction:
The reduction is carried out in a conventional manner comprising chemical reduction and catalytic reduction.



   Suitable reducing agents for use in chemical reduction are a combination of a metal (e.g. tin, zinc, iron, etc.) or a metallic compound (e.g. chromium chloride, chromium acetate, etc.) and an organic or mineral acid (e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, l hydrochloric acid, hydrobromic acid, etc.),
Suitable catalysts a. used in catalytic reduction are conventional catalysts such as platinum catalysts (e.g. a plate

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 platinum, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.

   ), palladium catalysts (for example sponge palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulphate, palladium on carbonate of barium, etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g. reduced cobalt, nickel cobalt Raney, etc.), iron catalysts (eg reduced iron, Raney iron, etc.), copper catalysts (eg reduced copper, Raney copper, copper Ullman, etc.) and the like.



   The reduction is usually carried out in a conventional solvent which does not adversely affect the reaction such as water, methanol, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof.



   In addition, in the case where the above-mentioned acids to be used in the chemical reaction are in the liquid state, they can also be used as solvents. In addition, a suitable solvent for use in the catalytic reduction can be the solvent mentioned above, and another conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or their mixture.



   The reaction temperature of this reduction is not critical and the reaction is usually carried out at a temperature from cooling to heating.



   Method 3:
The compound (la) or its salt can be produced by introducing a group for protecting the carboxy radical in the compound (tub) or a reactive derivative on the carboxy group or its salt,
A suitable reactive derivative on the carbon xy group of the compound (Ib) may include a conventional derivative which can be applied to. this reaction such as a haul

  <Desc / Clms Page number 17>

 acid nure (e.g. acid chloride, acid bromide, etc.) or the like.



   The agent for introducing a carboxy protecting group to be used in this reaction can comprise a conventional esterifying agent such as an alcohol or its reactive equivalent (for example a halide, a sulfonate, a sulfate , a diazo compound, etc.) and the like.



   The present reaction can also be carried out in the presence of an organic or inorganic base such as an alkali metal (for example lithium, sodium, potassium, etc.), an alkaline earth metal (for example calcium, etc. .), an alkali metal hydride (e.g. sodium hydride, etc.), an alkaline earth metal hydride (e.g. calcium hydride, etc.), an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.), an alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, cesium carbonate, etc.), an alkali metal bicarbonate (e.g. sodium bicarbonate, sodium bicarbonate potassium, etc.

   ), an alkali metal alkylate (e.g. sodium methylate, sodium ethylate, potassium t-butoxide), an alkali metal alkanoate (e.g. sodium acetate, etc.), a trialkylamine ( e.g. triethylamine, etc.), 1, 8-diazabicyclo [5, 4, olundec-7-ene, pyridines (e.g. pyridine, lutidine, picoline, etc.), quinoline and the like, and can also be carried out in the presence of metallic iodide (for example sodium iodide, potassium iodide, etc.).



   In the case where alcohol is used as an agent for introducing a group protecting the carboxy group, the reaction can be carried out in the presence of a condensing agent such as a carbodiimide compound [for example N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N ', (4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbo-diinde, N, N'-diisopropylcarbodiimide, N-ethyl-N'- (3imethylaminopropyl) carbodiimide , etc.], an ester

  <Desc / Clms Page number 18>

 sulfonic acid derivative of N-hydroxybenzotriazole [eg z (4-chlorobe-nzenesulfonyloxy) -6-chloro-1H-benzotriazole, etc.] or the like.



   This reaction is usually carried out in a solvent which does not adversely influence the reaction such as acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, l acetate, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, pyridine, hexamethylphosphoramide, etc. or their mixture.



   The reaction temperature is not critical, and the reaction is carried out in many cases under cooling.
 EMI18.1
 saying, room temperature or heating.



  Method 4:
The compound (Id) or its salt can be prepared by subjecting the compound (Ic) or its salt to a reaction for removing the protecting group from the carboxy radical
2 in Rb.



   This reaction is carried out by a conventional process such as hydrolysis, reduction and the like.



   The hydrolysis and reduction process and the reaction conditions (for example the reaction temperature, the solvent, etc.) are substantially the same as those illustrated for the reaction for removing the protecting group from the carboxy radical of the compound (Ia ) in process 2, and therefore we must refer to it for an explanation.



   The desired compound (1) can be transformed into its pharmaceutically acceptable salt in a conventional manner.



   The methods for the preparation of the starting compound are explained in detail in the following.



  Method A;
Compound C; Vfi) or its salt can be produced by reacting the compound. ê (IVa) or its reactive derivative on the carboxy group, or its salt, with the compound (V) or its reactive derivative on the hydroxy group, or its salt,

  <Desc / Clms Page number 19>

 
The suitable reactive derivative on the carboxy group of the compound (IVa) can comprise the same as that indicated by way of example for the compound (. Ib) in process 3.



   The suitable reactive derivative on the hydroxy group of the compound (V) may comprise the compound (V) whose hydroxy group is substituted by an acid residue such as a halogen (for example chlorine, bromine, iodine, etc. ) or the like.



   Suitable salts of compounds (IVa) and (IVb) can comprise the same salts as those indicated by way of example for compound (I) and a suitable salt of compound (V) can comprise the same salt with a base as that indicated by way of example for compound (1).



   This reaction is carried out by the same method as that illustrated for method 3, and consequently, one must refer to this explanation with regard to the reaction condition (for example the reaction temperature, the solvent, the base, etc. ).



  Method B- (T):
The compound (VII) or its salt can be produced by reacting the compound (IV) or its reactive derivative on the amino group or its salt with the compound (VI) or its reactive derivative on the carboxy group or its salt.



   The suitable reactive derivative on the amino group of the compound (IV) can comprise a conventional derivative, for example, a silyl derivative formed by the reaction of the compound (IV) with a silyl compound such as trimethylsilylacetamide, bis (trimethylsilyl) acetamide, bis (trimethylsilyl) urea and the like, and a suitable reactive derivative of the compound (VI) can comprise an acid halide such as an acid chloride, an acid bromide or the like which can be prepared by diketene and halogen reaction,
A suitable salt of the compound (V) can comprise the same salt as that indicated by way of example for the compound Cr) and suitable salts of the compounds (var)

     and

  <Desc / Clms Page number 20>

 (VII) can comprise the same salt with a base as that indicated by way of example for the compound (I).



   The reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride , tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, hexamethylphosphoramide, etc., or a mixture thereof.



   The reaction temperature is not critical and the reaction is usually carried out at a temperature from cooling to heating.
 EMI20.1
 



  Method B:
The compound (II) or its salt can be produced by reacting the compound (VII) or its salt with a nitrosating agent.



   A suitable nitrosating agent can include nitrous acid and its conventional derivatives such as a nitrosyl halide (e.g. nitrosyl chloride, nitrosyl bromide, etc.), an alkali metal nitrate (e.g. nitrite of sodium, potassium nitrite, etc.), alkyl nitrite (e.g., butyl nitrite, pentyl nitrite, isamyl nitrite, etc.) and the like.



   In the case where a nitrous acid salt or its alkali metal salt is used as a nitrosating agent, the reaction is preferably carried out in the presence of an acid such as an organic or mineral acid (for example hydrochloric acid , sulfuric acid, formic acid, acetic acid, etc.).



   This reaction can preferably be carried out in the presence of an activated methylene compound such as acetylacetone, ethyl acetoacetate and the like.



   This reaction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran, methylene chloride, or a mixture of these products.

  <Desc / Clms Page number 21>

 



   The reaction temperature is not critical and the reaction is preferably carried out in the range from cooling to room temperature,
The compound (II) of this reaction can include the syn isomer, the anti isomer and their mixture on the Rydroxytmino group, and this compound can be represented by the partial formula
 EMI21.1
 
The desired compound (I) and its pharmaceutically acceptable salt of the present invention are new and have a strong antimicrobial activity, inhibiting the growth of a large number of pathogenic microorganisms including Gram-positive and Gram-negative microorganisms and are useful as agents. antimicrobials, especially for oral administration.



   To show the usefulness of the desired compound (I), the experimental data on the urinary excretion of a representative compound (I) of the present invention are presented in the following.



  Urinary excretion test (1) Experimental procedure
The test compound (100 mg / kg) was administered orally to groups of three rats, and urine samples were collected every 0-24 hours.



  (2) Experimental compound
 EMI21.2
 (A) pivaloyloxymethyl 7-3-vinyl-3-cephem-4-carboxylate (syn isomer) (hereinafter referred to as compound A) (B) 7- (2-aminothiazol4-yl) hydroxyiminoacetamidoJ-2-vinyl -3-cephem-4-carboxylate of 1-DL-ethoxycarbonyloxyethyl (syn isomer) (hereinafter by compound B).



  (3) Experimental results The percentage of urinary excretion value

  <Desc / Clms Page number 22>

 is shown in the following table.
 EMI22.1
 
 <tb>
 <tb> Compound <SEP> Excretion <SEP> urinary <SEP> C%) <SEP>
 <tb> A <SEP> 54, <SEP> 09 <SEP>
 <tb> B <SEP> 26, <SEP> 0 <SEP>
 <tb>
 
For therapeutic administration, the desired compound (I) and its pharmaceutically acceptable salt of the present invention are used in the form of a conventional pharmaceutical preparation which contains the compound as active ingredient, mixed with pharmaceutically acceptable carriers such as organic or mineral liquid or solid excipients which are suitable for oral, parenteral and external administration.

   The pharmaceutical preparations can be in solid form, such as tablets, granules, powders, capsules or a liquid form such as solutions, suspensions, syrups, emulsions, lemonades and the like.



   If necessary, auxiliary preparations, stabilizers, wetting agents and other commonly used additives such as lactose, citric acid, tartaric acid, may be included in the above preparations. stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar-agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol and the like.



   While the dose of compound (1) may vary depending on and also depend on the age, conditions of the patient, a kind of disease, a kind of compound (I) to be applied, etc., in general, amounts ranging from 1 mg to about 4,000 mg or even more per day can be administered to a patient. An average single dose of
 EMI22.2
 about 50 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the desired compound (Z) of the present invention can be used to treat diseases causing infections due to pathogenic microorganisms.

  <Desc / Clms Page number 23>

 



   The following preparations and examples are given for the purpose of illustrating the present invention.



  Preparation 1
1-DL-iodoethyl ethyl carbonate (7.32 g) was added all at once a. an acid solution
 EMI23.1
 7-amino-3, -vinyl-r3-cepI (4.52 g) and 1, 7-diazabicyclo 0] (4.5 ml) in! em-4-carboxylic N, N-dimethylacetamide (45 ml) while cooling with ice. After the mixture was stirred for 45 minutes 0-3QC, the reaction mixture was poured into ice-water (200 ml) and extracted with ethyl acetate (200 ml). The organic extract was washed with water and brine, dried over magnesium sulfate and concentrated to a quarter of the original volume. The concentrate was added to concentrated hydrochloric acid (2 ml).

   The resulting precipitate was collected by filtration, washed with ethyl acetate and air dried to give chlorine.
 EMI23.2
 DL-1-ethoxycarbonyloxyethyle 7-amino-3-vinyl-3-cephem-4-carboxylate hydrate (2,66 g).



   IR (Nujol) cm: 3400, 1775,1755, 1720
NMR (DMSO-d6) #: 1.27 (3H, t, J = 7Hz),
1.53 (3H, d, J = 6Hz), 3.93 (2H, m),
4.23 (2H, q, J = 7Hz), 5.0-6.0 (4H, m),
6, 7-7, 2 (2H, m), 8.0-10, 0 (2H, wide m).



  Preparation-2
Benzhydryl 7-amino-3-vinyl-3-cephem-4carboxylate hydrochloride (150 g) and trimethylsilylacetamide (189 g) were dissolved in ethyl acetate (1.5 liters), and the solution was cooled to -20 C. 4-bromoacetoacetyl bromide was added, which was obtained from diketene (39 g) and bromine (75 g) in methylene chloride (200 ml) at, 200C and the mixture was stirred at -10 C for 1 hour, The reaction mixture was poured into a mixture of methylene chloride (2 liters) and 1 liter CI water), and the organic layer was separated, followed by washing with water and with an aqueous solution of sodium chloride.

   After

  <Desc / Clms Page number 24>

 as the solvent was removed in vacuo, the resulting precipitates were washed with ethyl acetate, and then dried to give benzhydryl 7- (4-bromoacetoacetamido) -3- vinyl-3-cephem4-carboxylate ( 171 g), p. f.



   133-1370C (decomposition).



   IR (Nujol) cm: 3270, 1765, 1705, 1650, 1550
NMR (DMSO-d6) Q: 3, 5 4, 5 (6H, m), 5.2-6, 0 (4H, m), 6.83 (1H, m), 7.00 (1H, s) ,
7.45 (ION, m), 9.25 (li, d, J = 8Hz).



  Preparation 3
The following compound was obtained in a way
 EMI24.1
 similar to that of preparation 2.



  DL-1-ethoxycarbonyloxyethyl 7- (4-bromoacetoacetamido) '- 3-vinyl-3-cephem-4-carboxylate.



  IR (Nujol): 1780, 1760, 1270, 1080
NMR (DMSO-d6) #: 1, 27 (3H, t, J = 7Hz),
1.53 (3H, d, J = 6Hz), 3.93 (2H, m), 4.17 (2H, s), 4.23 (2H, q, J = 7Hz),
4.33 (2H, s), 5.0-6.0 (4H, m),
6, 5-7, 2 (2H, m), 9.17 (1H, d, J = 8Hz).



  Preparation 4
 EMI24.2
 To a solution of benzhydryl benzhydryl 7- 3-vinyl-3-cephem-4-carboxylate (40 g) in methylene chloride (400 ml) and acetic acid (200 ml) was added dropwise solution of sodium nitrite (7.5 g) in water (50 ml) at -10 to -5 ° C, and the mixture was stirred at -50C for 30 minutes. After addition of urea (7 g) and stirring at room temperature for 30 minutes, water (400 ml) was added to the reaction mixture.

   The organic layer was separated, washed with water and a 10% aqueous solution of sodium chloride, and dried over magnesium sulfate,
Removal of the solvent gave the solid, which was dried in vacuo to obtain the benzhydryl 7- (4-bromo-2hydroxyiminoacetoacetamido) -3-vinyl-3-cephem-4-carboxylate (48 g), p . f, 105-108 C.



     IR (Nujol): m-1: 3250, 177qat 1705.1665, 1540

  <Desc / Clms Page number 25>

 NMR (DMSo-d6) #: 3.80 (2H, m), 4.67 (2H, s),
5.2-6, 2 (4H, m), 6.80 (1H, m),
7.00 (1H, s), 7.45 (1OH, m),
9.42 ass, d, J = 8 Hz), 13.20 (1H, s).



   EXAMPLE 1 To a solution of 7- (4-bromo-2-hydroxyiminoacéto-
 EMI25.1
 acetamÌdo) benzhydryl cephem-4carboxylate (48 g) in N, dimethylacetamide (200 ml), -3-vinyl-3 was added thiourea (7.0 g) at 5 C, and the mixture was stirred at room temperature for one hour. After the reaction mixture was poured into a 3% aqueous solution of sodium bicarbonate (2 liters), sodium chloride (150 g) was added to it. The precipitates were collected by filtration and then dissolved in a mixture of acetone (200 ml) and ethyl acetate (500 ml).



  The separated organic layer was washed with an aqueous solution of sodium chloride, followed by evaporation. The resulting precipitates were collected by filtration, washed with ethyl acetate and diethyl ether and dried in vacuo to give 7- [2- (2-aminothiazol-4yl) -2-hydroxyiminoacetamido] -3 -benzhydryl-3-cephem-4-carboxylate (syn isomer) (16.9 g), p. f. 133-136 oC.



   IR (Nujol): cm; 3200.1780, 1720.1670,
1610
 EMI25.2
 NMR (DMSO-d6) 6: 75 (2H, m), 5, 2-6, 1 (4H, 6, 6, 75 (1H, m), 7.00 (1H, s), 7, 20 (2H , m), 7, 34 (lOH, m), 9, 50 (1H, d,
3, J = 8Hz).
EXAMPLE 2
 EMI25.3
 The following compounds were obtained in a similar manner to that of Example 1 (1) DL-1-ethoxycar- 7 [2-aminothiazol-4-yl) hydroxyiminoacetamidoJ-3-vinyl-3-cephem-4-carboxylate (2bonyloxyethyl (syn isomer).



  IR (Nujol) cm-1; 3300, 1780, 1750, 1670
 EMI25.4
 ID1N CDMSO-d6) 7Hz), 1, 6Hz),, 4, 7Hz), 5, 1-6, m),

  <Desc / Clms Page number 26>

 $; 1.17 (3H6.63 (1H, s), 6.7-7.3 (4H, m),
9.45 (1H, d, J = 8Hz), 11.33 (1H, s) (2) 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-vinyl -3-cephem-4-t-butoxycarbonylmethyl carboxylate (syn isomer)
 EMI26.1
 IR (Nujol) cmi, IR 3300, 3170, 1780, 1730, 1665, 1620 (3) 7-aminothiazol-4-yl) -2hydroxyiminoacêtamido] - 3-vinyl-3cêpn. of DLl-propionyï- (Nujol) cmoxyethyl (syn isomer) IR (Nujol) cm: 3300, 3200, 1780, 1765,1720,
 EMI26.2
 1710, 1660, (4) le 7 [2 amìnothiazol4yl) 2hydroxyiminoacétamido] -3-vinyl-3cêphem-4-carboxylate de pìvaloyloxymé-
1630.thyle (syn isomer) IR (Nujol) cm-1:

   3400, 1785, 1750, 1670, 1615,
1530, 1310, 1220
 EMI26.3
 (5) 7- 'aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-caroxylate of palmìtoyloxy- [2- (2methyl (syn isomer) IR (Nujol) cm: 3300, 1775, 1670, 1615, 1530,
1350.1210
 EMI26.4
 (6) 7- [2-2-aminothiazol-4-yl) do] -3-vinyl-3-cephem-4carboxylate of (5-methyl-2- -2-hydroxyiminoacetami-oxo-1,3-dioxol- 4-yl) methyl (syn isomer) IR (Nujol) cm: 3300,1812, 1772,1730, 1668,
1611
 EMI26.5
 (7) phthalid-3-yl 7- [2- do] -3-vinyl-3-cephem-4-carboxylate (syn isomer) IR (Nujol) cm '3200 (wide), 1772 (wide),
1728 (shoulder), 1660.1620 (8) le 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacétamido] -3-vinyl-3-cephem-4-carboxymethyl carboxymate (syn isomer )
IR (Nujol) cm-1:

   1765 (large), 1720, 1660 (large) (9) sodium 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-vinyl-3-cephem-4-carboxylate (syn isomer) -1 IR (Nujol) cm: 3200, 1760,1660, 1600

  <Desc / Clms Page number 27>

 
EXAMPLE 3
Benzhydryl benzhydryl 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylate (68.5 g) was added by part-to-mixture of 2,2,2-trifluoroacetic acid (60 ml) and ani-, sol (60 ml) at 5-7 C and the mixture was stirred at 50C for one hour. The reaction mixture was added dropwise to diisopropyl ether (1.5 liters), followed by collection of precipitates by filtration.

   After dissolving in a mixture of tetrahydrofuran (100 ml) and ethyl acetate (100 ml), the solution was extracted with an aqueous solution of sodium bicarbonate. The resulting aqueous layer was adjusted to pH 5.0 with 10% hydrochloric acid, washed with ethyl acetate and then chromatographed on aluminum oxide. Elution was carried out with an aqueous solution at
3% sodium acetate, and the fractions containing the desired compound were pooled. After adjusting to pH 6.0 with 10% hydrochloric acid, the aqueous solution was again chromatographed on activated charcoal.

   Elution was carried out with a 20% aqueous solution of acetone and the combined fractions were concentrated in vacuo and then lyophilized to give 7- [2- (2-aminothiazol-4-yl) -2- hydroxyiminoacetamido] -3-vinyl- 3-cephem-4-sodium carboxyla te (syn isomer) (14.4 g), which was broken down from 220 C.



   IR (Nujol) cm: 3200.1760, 1660.1600
NMR CD20) 3.67 (2H, s), 5.2-5, 7 (3H, m),
5.83 (1H, d, J = 5Hz), 6.80 (1H, m),
7.00 (1H, s).



   EXAMPLE 4
1-DL-iodoethyl ethyl carbonate (22 g) was added dropwise to a solution of 7- [2- (2- aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl- Sodium 3-cephem-4-carboxylate (syn isomer) (15 g) in N, N-dimethylacetamide (120 ml) at 5-70C, and the mixture was stirred at SOC for 30 minutes. To the reaction mixture was added ethyl acetate (200 ml), followed

  <Desc / Clms Page number 28>

 filtration. The filtrate was washed with water and with an aqueous solution of sodium chloride and then dried over magnesium sulfate.

   After removal of the solvent, the residue was washed with ethyl acetate and dried in vacuo to give 7- [2- (2-aminothiazol-4-yl) -
 EMI28.1
 DL-1-ethoxycarbonyloxyethyl 2-hydroxyiminoacetamido] -3-vinyl-3-cephem4-carboxylate (syn isomer) (7.4 g), p. f. 126 130 C.



  IR (Nujol) cm: 3300, 1780, 1750, 1670, 1620 NMR 1, 17 (3R, t, J = 7Hz), 50 (3H, d, J = 6Hz), 3.75 (2H, m), 4 , 13 (2H, q, J = 7Hz),
5.1-6.0 (4H, m), 6.65 (1H, s), 6.7-7.3 (4H, m), 9.45 (1H, d, J = 8Hz), 11, 33 (1H, s).



   EXAMPLE 5 Cesium carbonate (2.06 g) was added to
 EMI28.2
 a solution of 7-iminoacetamido] -3-vinyl-3-cephem-4-carboxylic acid syn) (5 g) in N, N-dimethylacetamide (50 ml) at 25 C.



   The mixture was stirred at room temperature for 1 hour and cooled on an ice bath. To this cooled mixture, ethyl carbonate and 1-DL-iodoethyl (9.2 g) was added all at once, and the mixture was stirred at 0-30C for 40 minutes. To the reaction mixture was added ethyl acetate (300 ml), which was followed by filtration. The filtrate was washed with water twice and with brine, treated with active charcoal, and dried over magnesium sulfate.



  After removing the solvent in vacuo, the residue was washed with diisopropyl ether and air dried
 EMI28.3
 to give DL-1-ethoxy- [2- (2-aminothiazol-4-yl) -2-hydroxyimino-carbonyloxyethyl (syn-isomer) 7-acetamido] -3-vinyl-3-cephem-4-carboxylate 4.6 g), p. f. 126 130 C.



   IR (Nujol) cm ': 3300, 1780,1750, 1670
NMR (DMSO-d6) ô: 1.17 (3H, t, J =: 7Hz), 1.50 (3R, d, J::; 6-Rz), 3.75 (2H, m), 4, 13 (2H, q, J = 7Hz), 5, 1-6, 0 (4H, m),
6, 63 (1H, s), 6, 7-7, 3 (4H, m),

  <Desc / Clms Page number 29>

 
9.45 (1H, d, J = 8Hz), 11, 33 (1H, s).



   EXAMPLE 6
Potassium iodide (4.0 g) was added a. a solution of t-butyl chloroacetate (1.2 g) in N, N-dimethylacetamide (50 ml) and the mixture was stirred for 40 minutes at room temperature. The precipitate was separated by filtration. To the filtrate was added 7- [2- (2-aminothiazol-4-yl) -2-hydroxyimino-
 EMI29.1
 acetamido] -3-vinyl3 cephem-4 potassium carboxylate (isoc mother syn) (3.2 g) at room temperature and the mixture was stirred for 1 hour and a half at the same temperature.

   The reaction mixture was added to a mixture of water and ethyl acetate and the mixture was adjusted to pH 7.0 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated to
 EMI29.2
 give 7- [2-aminothiazol-4-yl) do] -3-vinyl-3-cephem-4-carboxylate t-butoxycarbonylmethyl (syn isomer) (2.0 g).



   IR (Nujol) cm: 3300,3170, 1780,1730, 1665,
1620
NMR (DMSO-d6) 6: 1, 43 (9H, s), 3.76 (2H, q,
J = 18, OHz), 4.73 (2H, s), 5.24 (1H, d,
J = 5.0 Hz), 5.38 (1H, d, J = ll, OHz), 5.68 (1H, d, J = 18, OHz), 5.82 (1H, dd, J = 5, OHz,
8, OHz), 6.66 (1H, s), 7.03 (1H, dd,
J = ll, OHz, 18, OHz), 9.46 (1H, d, J = 8, OHz)
EXAMPLE 7
 EMI29.3
 DL-1-propionylo- (2-aminothiazol-4-yl) -2-hydroxyiminoaceous-xyethyl (syn isomer) (7- [2- tamido] -3-vinyl-3-cephem-4-carboxylate) g) was obtained by reacting 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylic acid (syn isomer) 15 g ) with DL-1-bromoethyl propionate (4.56 g) in a manner similar to that of Example 5.

   



   IR (Nujol) cm: 3300, 3200,1780, 1765,
 EMI29.4
 1720, 1710, 1660, 1630 NMR (DMSO-d6) 1.03 (3H, t, J = 7Hz), 1.48 (3H, h

  <Desc / Clms Page number 30>

 d, J = 6Hz), 2.38 (2H, q, J = 7Hz), 3.53 and
3.97 (2H, ABq, J = 18Hz), 5.23 (1H, d, J = 5Hz), 5.4, (1H, d, J = 11Hz), 5.65 (1H, d, J = 18Hz ),
5.85 (1H, dd, J = 8Hz, 5Hz), 6.67 (dorm)
6.83 (1H, dd, J = 18Hz, 11Hz), 6.93 (1H, q,
J = 6Hz), 7.1 (2H, broad s), 9, 43 (1H, d, J = 8Hz), 11, 33 (1H, s).



   EXAMPLE 8
Pivaloyloxymethyl (syn isomer) pivaloyloxymethyl 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylate (1.24 g) was obtained by reacting 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (3 g) with iodomethyl pivalate ( 5.05) in a manner similar to that of Example 5, p. f. 90-100 C (decomposition).



   IR (Nujol) cm: 3400,1785, 1750,1670, 1615,
1530.1310, 1220 NMR (DMSO-d6) #: 1, 14 (9H, s), 3.58 and 3.97 (2H, ABq, J = 18Hz), 5.24 (1H, d, J = 5Hz ), 5.39 (1H, d, J = 11Hz), 5.7-6.0 (3H, m), 5.77 (1H,
 EMI30.1
 d, J = 17Hz), 6.70 (1H, s), 6.83 dd, J = llHz, 17Hz), 7.12 (2H, large s),
J = 8Hz), 16.24 (1H, s).



   EXAMPLE 9
Palmitoyloxymethyl 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoaceous-tamido] -3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.86 g) was obtained making react
 EMI30.2
 7- [2- mido] -3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (3 g) with iodomethyl palmitate (4.13 g) in a similar manner to that from example 5, p, f. 90-105 C (decomposition).



   IR (Nujol) cm-1: 3300, 1775,1670, 1615, 1530,
1305.1210
 EMI30.3
 NMR (DMSO-d) 7 (26H, m), 2, 3-2, 5 C2H, m), and 3, 5, 21 (1H, d, J = 5Hz ', 5. (3H, m), 5 , 75 (IK, d, J17Hz), 6,

  <Desc / Clms Page number 31>

 
 EMI31.1
 EXAMPLE 10 A solution of potassium 7- 2-hydroxyiminoacetamido3-3-vinyl-3 cephem-4-carboxylate (2.0 g) of N, N-dimethyl-
6 t 1, 1-1, acetamide (30 ml), 4-bromomethyl-5-methyl-1, 3-dioxol-2-one (1.0 g) was added while cooling with ice with stirring . The reaction mixture was stirred at the same temperature for 30 minutes. The resulting mixture was poured into ethyl acetate (200 ml) and the organic solution was washed with water three times. The separated organic layer was dried over magnesium sulfate and concentrated under reduced pressure.



  The residue was subjected to column chromatography
 EMI31.2
 on silica gel (50 g) to give 7- [2- thiazol-4-yl} 4-carboxylate of (5-methyl-2-oxo-1, 3-dioxol-4-yl) methyl (syn isomer ) (0.62 g),
IR (Nujol) cm: 3300,1812, 1772,1730,
1668, 1611
NMR (DMSO-d6) 6: 2, 17 (3H, s), 3.52 (3.98 (2H,
ABq, J = 17Hz), 5.15 (2H, s), 5.20 (1H, d, J = 5Hz), 5.30 (1H, d, J = llHz), 5.63 (1H, d,
J = 17Hz), 5.76 (1H, dd, J = 5Hz, 8Hz), 6.63 (1H, s), 6.83 (1H, dd, J = llHz, 17Hz), 9.42 (1H, d, J = 8Hz), 11.3 (1H, s).



   EXAMPLE 11
Phthalid-3-yl 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.05 g) was obtained by reacting potassium 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3vinyl-3-cephem-4-carboxylate (1.0 g) with 3- bromophthalide (0.9 gases in a manner similar to that of Example 10,
IR CNujol) cm ': 3200 (wide), 1772 (wide),
1728 (shoulder), 1660 1620 MN (DMSO-d6):

   3.70 (2H, m), 5.18 Cula, d, J = 5Hz), 5.43 (1H, d, J = 11Hz), 5.73 (1H, d,
 EMI31.3
 Jl7ffz ', 5ffz, 75

  <Desc / Clms Page number 32>

    5, 83 (1H, dd, J (1HL, s), 6, 77, 2 (2H, m), 7, 668, 0 (6H, m), 9, 87 (1H, d, J = 8Hz)
EXAMPLE 12
Trifluoroacetic acid (5.4 ml) was added to a suspension of t- 7- [2- (2-aminothiazol-4-yl) -2hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylate butoxycarbonylmethyl (syn isomer) (1.8 g) in methylene chloride (4 ml) and anisol (1.8 ml) at room temperature and the mixture was stirred for 2 hours at the same temperature.



   To the resulting solution was added diisopropyl ether and the mixture was stirred. The resulting precipitates were collected by filtration and washed with diisopropyl ether. Precipitates
 EMI32.1
 were added to a mixture of ethyl acetate and water and the mixture was adjusted to pH 7 with a 20% aqueous solution of sodium carbonate with stirring. The separated aqueous layer was adjusted to pH 2.2 with 10% hydrochloric acid while cooling with ice. The precipitate was collected by filtration, washed with ice and water and dried over peiitoxy-
 EMI32.2
 of phosphorus in vacuo to give 7-zol-4-yl) carboxymethyl carboxylate (syn isomer) (0.73 g).



   IR (Nujol) cm: 1765 (wide), 1720.1660 (wide)
 EMI32.3
 NMR 6: 3.76 (2H, q, J = 18, OHz), 4.76 (2H, s), 5.24 (1H, d, J = 5, OHz), 5.37 (1H, d, J = ll, OHz), 5.86 (1H, d, J = 17, OHz), 7.83 (1H, dd, J = 5, OHz, 8, OHz), 6.69- (1H, s) , 6, 67 (3H, m), 9, 50 (1H, d, J8, EXAMPLE 13, '"A. 7-yl solution) -' 2hydroxytnnnoacêtamido] -3-vnyl-3-cephem-4-carbQxylate DL-1-ethoxycarbonyloxyethyl syn) (1 g) a (DMSO-d6) mixture of ethyl acetate (50 ml) and ethanol (2 ml), concentrated hydrochloric acid (0.3 ml) in

  <Desc / Clms Page number 33>

 cooling with ice and the mixture was stirred for 10 minutes at-0-3QC. To the solution was added diisopropyl ether (50 ml) and the resulting precipitate was collected by filtration,

   washed with ethyl acetate and air dried to give 7-E2- (2-amino-
 EMI33.1
 thiazol-4-yl) em-4-carboxylate of DL-lethoxycarbonyloxyethyl as hydrochloride (syn isomer) (0.8 g).



   IR (Nujol) cm: 3100,1780, 1750, 1640
NMR (DMSO-d6): 1.23 (3H, t, J = 7Hz), 1.53 (3H, d, J = 6Hz), 3.75 (2H:, m), 4.20 (2H, q ,
J = 7Hz), 5.0-6.0 (6H, m), 6.83 (1H, s),
6.7-7.2 (2H, m), 9.7 (1H, d, J = 8Hz), 12.5 (1H, large s)
EXAMPLE 14
To a solution of benzhydryl 7- (4-bromoacetoacetamido) - 3-vinyl-3-cephem-4-carboxylate (10 g) in a mixture of methylene chloride (70 ml) and acetic acid (25 ml), isoamyl nitrite (3.5 ml) was added dropwise at -3 to -5 C. The mixture was stirred for 40 minutes at -5 ° C., followed by addition of acetylacetone (4 g ) and stirring for 30 minutes at 5 C.



  To the reaction mixture, thiourea (3 g) was added and, after stirring for 3 hours, was added
 EMI33.2
 drop with ethyl acetate (70 ml) and diisopropyl ether (100 ml). The resulting precipitate was collected by filtration, and dried in vacuo to give 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylate hydrobromide. benzhydryl (syn isomer) (11.7 g).

   3 g of this product were added in parts to a mixture of 2,2,2-trifluoroacetic acid (5 ml) and anisol (5 ml) between 5 and 70C. After stirring for 1 hour at 50C, the reaction mixture was added dropwise to diisopropyl ether (150 ml). The resulting precipitate was collected by filtration and dissolved in a mixture of tetrahydrofuran (10 ml) and ethyl acetate (10 ml). The organic layer was extracted with an aqueous solution of sodium bicarbonate.

   The extract

  <Desc / Clms Page number 34>

 was washed with ethyl acetate retaining the pff value a. 5 and then adjusted to a pH of 2.2 with 10% hydrochloric acid. This solution has been
 EMI34.1
 tem for 1 hour at OOC, and the crystals obtained were collected by filtration and dried under vacuum to give 7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoaceous-tamido] -3- acid vinyl-3-cephem-4-carboxylic (syn isomer) (0.79 g).



   IR (Nujol) cm: 3300,1780, 1665,1180, 1130.



   EXAMPLE 15
 EMI34.2
 To a solution of benzhydryl 7-nyl-3-cephem-4-carboxylate (15 g) in a mixture of methylene chloride (100 ml) and acetic acid (30 ml), a solution was added dropwise. sodium nitrite (2.8 g) in water (5 ml) at -10 to -15 C. The reaction mixture was stirred for 40 minutes at -5 C, followed by addition of acetylacetone (4 g) and then stirring for another 15 minutes at room temperature. The reaction mixture was poured into a mixture of water (200 ml) and methylene chloride (200 ml), and the organic layer was separated and washed with water. The solution was evaporated and the residue was dissolved in N, N-dimethylacetamide (40 ml).



  To this solution was added thiourea (3.4 g), and the mixture was stirred for 1 hour at room temperature, and poured into a mixture of tetrahydrofuran (150 ml), ethyl acetate (300 ml) and water (300 ml).



  The mixture was adjusted to pH 6.0 with an aqueous solution of soda razz. The separated organic layer was washed with an aqueous solution of sodium chloride at 20% successively and dried over magnesium sulphate. The solvent was removed by vacuum distillation, and the precipitate was collected by filtration and washed with ethyl acetate and diisopropyl ether. This precipitate was dried in vacuo to give 7- [2- (2 aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3- cephjem-4-carboxylate, benzhydryl (syn isomer) (8.5 g).

  <Desc / Clms Page number 35>

 



   IR (Nujol) cm: 3200, 1780, 1720, 1670,
1610
EXAMPLE 16
To a solution of 7- [2- (2-aminothiazol-4-yl) - 2-hydroxyimìnoacétamido] -3-vinyl-3-cephem-4-carboxylate (syn isomer) (5 g) in a mixture of anisol (20 ml) and acetic acid (5 ml), boron trifluoride etherate (5 ml) was added dropwise at 10 C. After stirring for 20 minutes at 10 C, the reaction mixture was was poured into a mixture of tetrahydrofuran (100 ml), ethyl acetate (100 ml) and water (100 ml) and then adjusted to pH 6.0 with 20% aqueous sodium hydroxide solution %. The resulting aqueous layer was separated and washed with ethyl acetate maintaining the pH value at 6.0. This solution was subjected to chromatography on aluminum oxide.

   The fractions eluted with a 3% aqueous solution of sodium acetate were pooled and adjusted to pH 5.0 with 10% hydrochloric acid. This solution was further chromatographed on a nonionic adsorption resin called "Diaion HP-20" (registered trademark, product manufactured by the company called Mitsubishi Chemical Industries). The fractions eluted with a 20% aqueous solution of acetone were combined, concentrated in vacuo and adjusted to a pH of 2.0 with 10% hydrochloric acid. The resulting precipitate was collected by filtration and dried under
 EMI35.1
 vacuum to give 7-hydroxyiminoacetamidoJ-3-vinyl-3-cephem-4-carboxylic acid [2- (2-aminothiazol-4-yl) -2- (syn isomer) (1.23 g).



   IR (Nujol) cm: 3300, 1780,1665, 1180,1130
 EMI35.2
 NMR (DMSO-d6) 6 3.76 (2H, ABq, J = 18Hz), 5.2, 6.0, (., M), 6.73 (us, s), 6.8 ".



      ; (3H, m), 9.5 (1H, d, J = 8Hz), 11.4 (1H, large s),
EXAMPLE 17 (1) Benzhydryl 7 amino-3-vinyl-3- cephem-4-carboxylate hydrochloride (1 kg) and 1,3-bis (tri-methylslylyl) urea (1.46 kg) were dissolved in tetrahy-

  <Desc / Clms Page number 36>

 drofuran (8 1) and the mixture was cooled to -20 C.



   To this solution was added 4-bromoacetoacetyl bromide obtained from diketene (224 ml) and bromine (147 ml) in methylene chloride at -20oC and the mixture was stirred for 30 minutes at -15 C. The reaction mixture was poured into a mixture of ethyl acetate (12 L) and water (6 L). The organic layer was separated, washed with an aqueous solution of sodium chloride and then evaporated in vacuo. The resulting precipitate was stirred in diisopropyl ether (10 L) for 1 hour at 0 C, and the crystals obtained were collected by filtration and dried in vacuo to give 7- (4-bromoacetoacetamido) -3-vinyl -3-cephem-4 benzhydrylcarboxylate (1.27 kg), p. f. 133-137 C (decomposition).



    (2) To a solution of benzhydryl 7- (4-bromoacétoacétamìdo) - 3-vinyl-3-cephem-4-carboxylate (500 g) in a mixture of methylene chloride (4.5 1) and acetic acid (1.7 g) a solution of sodium nitrite (93.2 g) in water (450 ml) was added drop between -15 and -22 C. The reaction mixture was stirred for 7 minutes at - 150C, followed by addition of ethyl acetoacetate (117 g) and then stirring for 5 minutes at room temperature.



   The reaction mixture was washed with water (6 1 x 2) and an aqueous solution of sodium chloride (6 l). To the separated organic layer was added thiourea (82.2 g) dissolved in N, N-dimethylacetamide (11) and the mixture was stirred for 1 hour at 36 ° C. After the methylene chloride had removed in vacuo, the residual oil was poured into a mixture of tetrahydrofuran (3, 5 1), ethyl acetate (7 1) and ice and water (4 1), This mixture was adjusted to pH 6.0 with an aqueous sodium hydroxide solution. 10%. The separated organic layer was washed with water (4 1 x 2) and an aqueous solution of sodium chloride.

   The solvent was removed by vacuum distillation and the crystals

  <Desc / Clms Page number 37>

 Siduels were stirred in a mixture of ethyl acetate (1.6 l) and diisopropyl ether (2.4 l) for 1 hour at 0 C. The crystals obtained were collected by filtration to give 7- Benzhydryl [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylate (syn isomer) (394.5 g).



   IR (Nujol) cm: 3200, 1780,1720, 1670,
1610
EXAMPLE 18
7- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylate DL-1-aceto-xyethyl (syn isomer) (1,12 g) was obtained by
 EMI37.1
 react 7-acetamido] -3-vinyl-3 cephem-4-carboxylic acid (syn isomer) (5 g) with DL-1-bromoethyl acetate (3.42 g) in the presence of cesium carbonate (2, 04 g) in a similar manner to that of Example 5.



   IR (Nujol) cm: 3300,1780, 1760,1670, 1210.



   The present invention is not limited to the exemplary embodiments which have just been described, it is on the contrary liable to modifications and variants which will appear to those skilled in the art,


    

Claims (1)

 CLAIMS 1-As a new industrial product, syn isomer of the compound having the formula;  EMI38.1  where R is the amino group or a protected amino group, and R2 is the carboxy group or a protected carboxy group, and its pharmaceutically acceptable salt.  2-A compound according to claim 1, characterized in that R1 is the amino group.  3-Compound according to claim 2, characterized in that it is formed by 7- [2- (2-aminothiazol-4yl) -2-hydroxyìmìnoacétamido] -3-vinyl-3-cephem-4-carboxylic acid ( syn isomer) or its sodium salt or its potassium salt.  4-Compound according to claim 2, character-  EMI38.2  2 se in that is an esterified carboxy group. 5-Compound according to claim 4, characterized in that is an alkoxy (lower) carbonylo-xyalkoxy (lower) carbonyl group.  6-A compound according to claim 5, characterized in that it is formed by 7- [2- (2-aminothiazol-4-yl) -  EMI38.3  2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxylate of 1-ethoxycarbonyloxyethyl (syn isomer) or its hydrochloride. 7 claim 4, characterized in that is an alkoxy alkoxy carbonyl group, 8-compound claim 7, in that it is formed by 7- [2- 2-hydroxyiminoacetamido] -3-vinyl-3- t-butoxycarbonylmethyl cephem-4-carboxylate (syn isomer).  <Desc / Clms Page number 39>    EMI39.1   9 according to claim 4, characterized in that is a carboxyalkoxy (lower) carbonyl group.    10-Compound according to Claim 9, characterized in that it is formed by 7- [2- (2-aminothiazol- 4-yl) -2-hydroxyìm9noacétamido] -3-vinyl-3-cephem-4-carboxylate carboxymethyl (syn isomer).  11-A compound according to claim 4, charac-  EMI39.2  2 terized in that is an alkanoyl (lower) alkoxy (lower) carbonyl group.    12-Compound according to claim 11, characterized in that it is formed by 7- [2- (2-aminothiazol-  EMI39.3  13-Compound according to claim 11, carac- -2-hydroxyiminoacetamido] -3-vinyl-3-cephem-4-carboxy-terized in that it is formed by the 4-yl) late propnyloxyethyl (syn isomer) Pivaloyloxymethyl 7- [2- (2-aminothiazol-4-yl) -2-hydroxyìminoacetamido] -3-vinyl-3-cephem-4-carboxylate (syn isomer).  14-Compound according to claim 4, character-  EMI39.4  2 laughed at what is an alkanoyl (upper) oxyalkoxy (lower) carbonyl group.    15-Compound according to Claim 14, characterized in that it is formed by 7- [2- (2-aminothiazol- 4-yl) -2-hydroxyìmìnoacétamido] -3-vinyl-3-cephem-4-carboxylate palmitoyloxymethyl (syn isomer).    16-Compound according to claim 4, character-  EMI39.5  2 laughed in that is a group (5-lower alkyl-2-oxo- R21, 3-dioxol-4-yl) (lower) alkoxy carbonyl.  17 - Compound according to claim 16, characterized in that it is formed by 7- [2- (2-aminothiazol-  EMI39.6  4-yl) -2-hydroxyiminoacetamidol-3-vinyl-3-cephem-4-carboxylate of (5-methyl-2-oxo-1, dioxol-4yl) 3-syn).    18 - Compound according to claim 4, character-  EMI39.7  2 laughed in that is the phthalidyloxycarbonyl group.  R217 - Compound according to Claim 18, characterized in that it is formed by 7- [2- (2-aminothiazol-4-yl) -2-hydroxyìmìnoacétamìdo] -3-vinyl-3-cephem-4- carbo-  <Desc / Clms Page number 40>  phthalid-3-yl xylate (syn isomer), proceeds to produce a syn isomer of the compound of formula:  EMI40.1  where RI is the amino group or a protected amino group, and 2 R is the carboxy group or a protected carboxy group, and its salt, characterized in that it consists in: reacting a compound of formula:  EMI40.2    EMI40.3  2 where is as defined above and X is a halogen, or its salt, with a compound of formula;  EMI40.4  where R1 is as defined above, to give a compound  EMI40.5  of formula:    EMI40.6    EMI40.7  1 or R and sound 2sel.    21-Process for the production of a syn isomer of the compound of formula () indicated in claim 20 and of its salt, characterized in that it consists in subjecting  <Desc / Clms Page number 41>  a compound having the formula:  EMI41.1  where R is as defined in claim 20, and R2 is a protected carboxy group, or its salt, in a reaction for removing the protecting group from the carboxy radical to give a compound of formula:  EMI41.2  where R1 is as defined above or its salt.    22 - Process for the production of a syn isomer of a compound as indicated in claim 20 and of its salt, characterized in that it consists in introducing a group for protecting the carboxy radical in a compound of formula:  EMI41.3  where R is as defined in claim 20, or its reactive derivative on the carboxy group, or its salt, to give a compound of formula:  EMI41.4    <Desc / Clms Page number 42>    EMI42.1  where is as defined in claim 20 and 2 is as defined in claim 21, or its salt.    23-Process for the preparation of a syn isomer of a compound of formula (I) indicated in claim 20 and of its salt, characterized in that it consists in subjecting a compound of formula;  EMI42.2  or R is as defined in claim 20, and  EMI42.3  R is a carboxy carbob nyl group, or its salt, in a reaction for removing the group protecting the carboxy radical in IL to give a compound having the formula:  EMI42.4  where R is as defined in claim 20, and  EMI42.5  2 a carboxyalkoxy (lower) carbonyl group, or c its salt.  24-Pharmaceutical composition, characterized in that it comprises, as active ingredient, a compound of claim 1 and a pharmaceutically acceptable salt of this compound, mixtures with pharmaceutically acceptable carriers.  25- Use of a compound of claim 1, and its pharmaceutically acceptable salt, characterized in that these products are used for the treatment of microbial infections,